The recent discovery of the reverse transcriptase inhibiting activity of various modified nucleosides and their actual and potential utility as therapeutic agents in the treatment of Acquired Immunodeficiency Syndrome (AIDS) related human immunodeficiency virus (HIV) infections, has stimulated interest in improved methods of preparing such modified nucleosides. Of particular interest are new methods of preparing 3'-azido-3'-deoxythymidine (AZT) and 3'-deoxy-3'-fluorothymidine (FLT) which have been reported to be potent inhibitors of HIV-induced cytopathogenicity. Extensive studies on the synthesis and biological activity of 3'-azido, 3'-amino, and 3'fluoro pyrimidine and purine 2',3'dideoxyribonucleoside analogues have been reported.
In general, methods of producing such 3'-substituted nucleosides have proceeded along two separate paths: (1) substitution of the 3'-OH function in a 2'-deoxynucleoside, as in the case of the synthesis of AZT or FLT from thymidine, or (2) preparation of a 3-substituted furanoside compound followed by the coupling of a suitable purine or pyrimidine base such as thymine. The latter method has certain advantages since it uses simpler starting materials and it provides for the easy substitution of a number of nucleophiles at the 3'-position to provide intermediates suitable for efficient coupling with purine or pyrimidine bases. The latter method therefore provides the greatest possibilities for synthesis of 3'-substituted nucleosides in large scale quantities.
Several methods for the synthesis of 3-substituted furanoside sugars have been described but they are complicated, and they require multiple steps and expensive reagents. Fleet, G. W. et al; Tetrahedron 1988, 44(2) 625-636 describes the synthesis of methyl 5-0-tert-butyldiphenylsilyl-2-deoxy-.alpha.(.beta.)-D-threopentofuranoside from D-xylose and its conversion to the azido, fluoro and cyano sugars followed by the subsequent coupling of these derivatives with protected thymine to give the thymidine compounds Bravo, P. et al., J. Org. Chem. 1989, 54, 5171-5176 describes the asymmetric synthesis of the 3-fluoro furanose sugars starting from a compound of the formula: ##STR1## which is monoalkylated on the fluorinated carbon with allyl bromide. Removal of the auxiliary sulfinyl group followed by a reductive work-up and oxidative cleavage of the double bond afforded the 5-0-benzoyl-2,3-dideoxy-3-fluoro-furanose.
Monosaccharides, containing an exocyclic double bond are also valuable, useful compounds for use in the synthesis of branched and functionally substituted carbohydrates. N. K. Kochetkov et al, Tetrahedron Letters, 22 (43), 4315-4318 (1981) describes the synthesis of several macrolide antibiotics employing carbohydrates during their synthetic construction.
However, tetrahydro-5-substituted-3-methylene-2-furanmethanols are new and not known as useful intermediates for the synthesis of 3'-substituted nucleosides.
The present invention describes an improved alternate method for the stereo and enantioselective synthesis of tetrahydro-5-hydroxy-3-methylene-2-furanmethanol and of tetrahydro-5-[lower alkoxy (C.sub.1 -C.sub.3)]-3-methylene-2-furanmethanol. The process is new, uncomplicated, uses a small number of steps and simple, inexpensive starting materials.